Obstructive sleep apnea is emerging as an important risk factor for hypertension, heart failure, and ischemic heart disease. The mechanisms linking obstructive sleep apnea to cardiac and vascular disease are poorly understood. Utilizing recent developments in neural circulatory control and in vascular biology, we have acquired exciting preliminary data that promise mechanistic insight into the association between sleep apnea and cardiovascular disease. These data suggest that patients with sleep apnea have: 1) increased sympathetic neural traffic, tachycardia, and marked impairment of heart rate and blood pressure variability; 2) impaired endothelial vasodilator function; 3) dramatic overnight increases in endothelin and cytokines, with reductions in both after acute continuous positive airway pressure (CPAP) therapy; and 4) a reduction in blood pressure and sympathetic drive after long-term CPAP therapy. These interesting findings have led us to propose the overall hypothesis that obstructive sleep apnea is associated with neural, vasoactive and inflammatory abnormalities, which may be implicated in cardiovascular dysfunction, and that these abnormalities are attenuated by long-term therapy with CPAP. We will test the following specific hypotheses: 1) That patients with sleep apnea have impaired neural mechanisms regulating circulatory control. 2) That patients with sleep apnea have impaired endothelial function, and increased production of endothelin, cytokines and leukocyte adhesion molecules. 3) That long term effective therapy with CPAP improves cardiovascular function by attenuation of these abnormalities in neural, vasoactive and inflammatory mechanisms. An important and novel strength of these studies is that the integrity of the hypotheses will be tested with careful exclusion of potential confounding variables such as obesity, hypertension, left ventricular dysfunction, exercise capacity and impaired glucose tolerance. This proposal builds on our broad experience in studies of both sleep apnea and neural circulatory control, and should contribute to the understanding and treatment of cardiac and vascular disease in patients with obstructive sleep apnea.